Statins as Immunomodulatory Agents

Mach, François

doi:10.1161/01.cir.0000129502.10459.fe

Cited by 83 publications

(63 citation statements)

References 26 publications

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“…This effect was dose dependent and was abrogated when statins were administered together with 200 μM mevalonate, a metabolite that reverses statin-mediated inhibition of the cholesterol synthesis pathway ( Figures 3A and 4A ). 27 Similar results were observed with another member of the statin class of drugs, atorvastatin (see supplementary Figures 1A and 2A online at www.ajtmh.org ).…”

Section: Resultssupporting

confidence: 81%

Statins Fail to Improve Outcome in Experimental Cerebral Malaria and Potentiate Toll-Like Receptor-Mediated Cytokine Production by Murine Macrophages

Helmers

Gowda²,

Kain

et al. 2009

The American Journal of Tropical Medicine and Hygiene

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Abstract. Cerebral malaria is responsible for a large proportion of the estimated one million deaths caused by Plasmodium falciparum malaria annually. This disease is associated with excessive pro-inflammatory cytokine production resulting from dysregulated host responses to infection. On the basis of reports indicating potent activity against host-mediated inflammatory disorders such as sepsis, we examined the activity of statins (3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors) on malaria-associated inflammation in vivo and in vitro . Simvastatin failed to improve survival or alter parasitemia in C57BL/6 mice infected with Plasmodium berghei ANKA, an experimental model of cerebral malaria. In vitro statin treatment potentiated production of tumor necrosis factor and interleukin-6 by murine peritoneal macrophages in response to P. falciparum glycosylphosphatidyl inositol, a Toll-like receptor 2 (TLR2) ligand. Statin treatment also potentiated pro-inflammatory cytokine production stimulated by a panel of TLR2 and TLR4 ligands. Our results indicate that statins fail to confer protection in experimental cerebral malaria and potentiate TLR-mediated proinflammatory cytokine production by primary murine macrophages.

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Section: Resultssupporting

confidence: 81%

Statins Fail to Improve Outcome in Experimental Cerebral Malaria and Potentiate Toll-Like Receptor-Mediated Cytokine Production by Murine Macrophages

Helmers

Gowda²,

Kain

et al. 2009

The American Journal of Tropical Medicine and Hygiene

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“…Laboratory investigations have shown that cessation of statin therapy results in rapid worsening of inflammatory parameters such as C‐reactive protein10, 11, 12 as well as endothelial function 13, 14. Exposure to statins in the acute phase of experimental stroke appears to promote angiogenesis and synaptogenesis,15 and additional pleiotropic statin effects such as vasodilatory and antithrombotic properties have been reported 16. These experimental observations are supported by clinical findings of improved outcomes with acute statin use in myocardial infarction,17, 18, 19 stroke,3, 4, 20, 21 and major vascular surgery 22, 23…”

Section: Discussionmentioning

confidence: 99%

Impact of Increased Early Statin Administration on Ischemic Stroke Outcomes: A Multicenter Electronic Medical Record Intervention

Flint

Conell

Klingman

et al. 2016

JAHA

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BackgroundStatin administration early in ischemic stroke may influence outcomes. Our aim was to determine the clinical impact of increasing statin administration early in ischemic stroke hospitalization.Methods and ResultsThis is a retrospective analysis of a multicenter electronic medical record (EMR) intervention to increase early statin administration in ischemic stroke across all 20 hospitals of an integrated healthcare delivery system. A stroke EMR order set was modified from an “opt‐in” to “opt‐out” mode of statin ordering. Outcomes were mortality by 90 days, discharge disposition, and increase in stroke severity. We examined the relationship between intervention and outcome using autoregressive integrated moving average (ARIMA) time‐series modeling. The EMR intervention increased both overall in‐hospital statin administration (from 87.2% to 90.7%, P<0.001) and early statin administration (from 16.9% to 26.3%, P<0.001). ARIMA models showed a small increase in the rate of survival (difference in probability [P diff]=0.02, P=0.016) and discharge to home or rehabilitation facility (P diff=0.04, P=0.034) associated with the intervention. The increase in statin administration <8 hours was associated with much larger increases in survival (P diff=0.17, P=0.033) and rate of discharge to home or rehabilitation (P diff=0.29, P=0.011), as well as a decreased rate of neurological deterioration in‐hospital (P diff=−0.14, P=0.026).ConclusionsA simple EMR change increased early statin administration in ischemic stroke and was associated with improved clinical outcomes. This is, to our knowledge, the first EMR intervention study to show that a modification of an electronic order set resulted in improved clinical outcomes.

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“…In addition to their cholesterol-lowering effect, recent reports suggest that statins also possess antiinflammatory and immunomodulatory actions. 37,38 Nevertheless, several adverse events have been reported, such as renal toxicity and rhabdomyolysis, in patients treated with statins. 39,40 Although the precise reason for these effects is not fully understood, it appears that they are in part the result of mitochondrial toxicity and selenoprotein deficiency.…”

Section: Fougerat Et Al Phosphoinositide 3-kinase-␥: Key To Atherosclmentioning

confidence: 99%

Genetic and Pharmacological Targeting of Phosphoinositide 3-Kinase-γ Reduces Atherosclerosis and Favors Plaque Stability by Modulating Inflammatory Processes

et al. 2008

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Background-The role of inflammation at all stages of the atherosclerotic process has become an active area of investigation, and there is a notable quest for novel and innovative drugs for the treatment of atherosclerosis. The lipid kinase phosphoinositide 3-kinase-␥ (PI3K␥) is thought to be a key player in various inflammatory, autoimmune, and allergic processes. These properties and the expression of PI3K␥ in the cardiovascular system suggest that PI3K␥ plays a role in atherosclerosis. Methods and Results-Here, we demonstrate that a specific PI3K␥ inhibitor (AS605240) is effective in murine models of established atherosclerosis. Intraperitoneal administration of AS605240 (10 mg/kg daily) significantly decreased early atherosclerotic lesions in apolipoprotein E-deficient mice and attenuated advanced atherosclerosis in low-density lipoprotein receptor-deficient mice. Furthermore, PI3K␥ levels were elevated in both human and murine atherosclerotic lesions. Comparison of low-density lipoprotein receptor-deficient mice transplanted with wild-type or PI3K␥-deficient bone marrow demonstrated that functional PI3K␥ in the hematopoietic lineage is required for atherosclerotic progression. Alleviation of atherosclerosis by targeting of PI3K␥ activity was accompanied by decreased macrophage and T-cell infiltration, as well as increased plaque stabilization. Conclusions-These data identify PI3K␥ as a new target in atherosclerosis with the potential to modulate multiple stages of atherosclerotic lesion formation, such as fatty streak constitution, cellular composition, and final fibrous cap establishment.

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Statins as Immunomodulatory Agents

Cited by 83 publications

References 26 publications

Statins Fail to Improve Outcome in Experimental Cerebral Malaria and Potentiate Toll-Like Receptor-Mediated Cytokine Production by Murine Macrophages

Statins Fail to Improve Outcome in Experimental Cerebral Malaria and Potentiate Toll-Like Receptor-Mediated Cytokine Production by Murine Macrophages

Impact of Increased Early Statin Administration on Ischemic Stroke Outcomes: A Multicenter Electronic Medical Record Intervention

Genetic and Pharmacological Targeting of Phosphoinositide 3-Kinase-γ Reduces Atherosclerosis and Favors Plaque Stability by Modulating Inflammatory Processes

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